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Category: genetics

Scientists discover the switch that revives exhausted cancer-fighting T cells

Scientists have uncovered new genetic rules that determine whether the immune system’s “killer” T cells remain powerful long-term defenders or become worn out and ineffective. By building a detailed genetic atlas of CD8 T cell states, researchers identified key molecular switches that push these cells toward either resilience or exhaustion. Remarkably, disabling just two previously unknown genes restored the tumor-killing power of exhausted T cells while preserving their ability to provide lasting immune protection.

Abstract: In 2015, Philip M

Murphy & colleagues reported on a patient with WHIM syndrome who was cured of the disease by a spontaneous somatic genetic event that deleted the mutant CXCR4 allele in a single hematopoietic stem cell.

Here, the team now show CRISPR silencing of the Cxcr4 overactive disease allele corrects leukopenia in a murine model of WHIM syndrome, demonstrating a new therapeutic strategy for dominant immune disorders.

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.

New cellular immunotherapy approach for Alzheimer’s disease

Alzheimer’s disease starts with a sticky protein called amyloid beta that builds up into plaques in the brain, setting off a chain of events that results in brain atrophy and cognitive decline. Microglia, immune cells that reside in the brain, are responsible for removing brain waste but can become dysfunctional when overwhelmed in the context of neurodegenerative disease.

To reduce the cleaning burden on microglia, first author transformed astrocytes, the most abundant cell type in the brain, into amyloid-cleaning machines. The author custom-designed and delivered a gene to astrocytes that codes for the chimeric antigen receptor (CAR) via a harmless virus injected into mice. The CAR, now present on the surface of astrocytes, enabled the cells to capture and engulf amyloid beta proteins. With their newly acquired ability, the astrocytes — generally responsible for keeping the brain tidy — concentrated their efforts on only cleaning amyloid beta plaques in mice prone to its buildup.

Mice carrying genetic mutations that increase people’s risk of developing Alzheimer’s disease develop amyloid beta plaques that saturate the brain by six months of age. The author injected two groups of mice with the virus carrying the CAR-expressing gene: young mice before they developed plaques and older mice with brains saturated with plaques, then, waited three months.

As the younger mice aged, the CAR-astrocytes prevented amyloid beta plaque development. At nearly six months of age, when untreated mice normally have brains saturated with harmful plaques, brains of treated mice were plaque-free. Meanwhile, older mice with plaque-saturated brains at the time of treatment saw a 50% reduction in the amount of amyloid beta plaques compared to mice receiving an injection of a virus lacking the CAR gene.

The researchers have filed a patent related to the approach used to engineer CAR-astrocytes.

“Consistent with the antibody drug treatments, this new CAR-astrocyte immunotherapy is more effective when given in the earlier stages of the disease,” said a co-author on the paper. “But where it differs, and where it could make a difference in clinical care, is in the single injection that successfully reduced the amount of harmful brain proteins in mice.” ScienceMission sciencenewshighlights.

Continue reading “New cellular immunotherapy approach for Alzheimer’s disease” | >

Genetic factors drive the link between cognitive ability and socioeconomic status

A new study of German twins suggests that the strong connection between a young adult’s cognitive ability and their future socioeconomic status is largely driven by their genes, rather than shared family environments or random life events.

Your gut microbes can be anti-aging—scientists are uncovering how to keep your microbiome youthful

People have long given up on the search for the Fountain of Youth, a mythical spring that could reverse aging. But for some scientists, the hunt has not ended—it’s just moved to a different place. These modern-day Ponce de Leóns are investigating whether gut microbes hold the secret to aging well.

The gut microbiome refers to the vast collection of microscopic organisms—bacteria, fungi, and viruses—that largely inhabit the colon. These microbes aid in digestion and produce molecules that affect your physiology and psychology. The composition of the microbiome is influenced by a combination of factors, including genetics, diet, the environment, medications, and age.

I’m a microbiology professor and author of “Pleased to Meet Me: Genes, Germs and the Curious Forces That Make Us Who We Are,” which describes how the gut microbiome contributes to physical and mental health. The discovery that the gut microbiome changes with age has ignited studies to determine whether the Fountain of Youth might be right under your nose, down inside your gut.

DNA barcoding reveals which gene-therapy nanoparticles reach targets in vivo

Drug delivery researchers have vastly improved the potential of genetic therapies by overcoming the challenge of consistently getting genes and gene-editing tools where they need to be within cells. Findings of the study spearheaded by Oregon State University College of Pharmacy graduate student Antony Jozić are published in Nature Biotechnology.

When gene therapies enter a cell, they are often sent to lysosomes, the cell’s trash and recycling centers, where therapeutic genetic material is broken down before it can work. For gene therapies to succeed, they must avoid disposal and reach the part of the cell where they can function.

Bringing the genetically minimal cell to life on a computer in 4D

This work represents a fundamental advance in understanding life’s basic principles. By building a cell from the bottom up—specifying every gene, protein, and reaction—researchers can test how life functions with minimal complexity. The simulation serves as a “digital twin” that allows scientists to probe questions impossible to address experimentally, such as how spatial organization affects cellular processes or how subtle parameter changes alter cell cycle timing.

Simulating the complete cell cycle of the minimal cell provides a platform to understand the progression of complete states over time. The spatial heterogeneity of the intracellular environment can strongly affect biochemical reactions that control phenotypes.

Real-world validation study of the LSC17 score for risk prediction in patients with newly diagnosed acute myeloid leukemia

The identification of patients with acute myeloid leukemia (AML) who may have resistant disease when treated with standard induction chemotherapy is still challenging: Murphy and colleagues present the first prospective, multicenter study aiming to evaluate the prognostic value of the leukemic stem cell 17-gene (LSC17) score in patients with newly diagnosed AML.

Acute myeloid leukemia (AML) patients exhibit diverse molecular and cytogenetic changes with heterogeneous outcomes. The functionally-derived LSC17 gene expression score has demonstrated strong prognostic significance in retrospective analyses of adult and pediatric AML cohorts, where above-median scores are associated with worse outcomes compared to below-median scores in intensively-treated patients. Here we used a laboratory-developed clinically-validated NanoString-based LSC17 assay to test the prognostic value of the LSC17 score in a prospective multicenter study of 276 newly-diagnosed AML patients. Each patient’s score was classified as high or low by comparison to a previously-established reference score. In the entire cohort, a high LSC17 score was associated with poor risk features, including advanced age and unfavorable genetic mutations. In the subset of 190 patients treated intensively, a high LSC17 score was associated with lower remission rates (63% vs. 94% after induction; P0.0001), presence of measurable residual disease (46% vs. 10%; P0.0001), and shorter overall survival (OS, 606 days vs. not reached; P=0.0004; hazard ratio

=2.16; 95% confidence interval [CI]: 1.39−3.35) and relapse-free survival (RFS, 541 days vs. not reached; P=0.001; HR=1.99; 95% CI: 1.29−3.08). In multivariable analysis considering age, white blood cell count and European LeukemiaNet 2022 risk groups, the LSC17 score remained an independent predictor of RFS and OS. Allogeneic stem cell transplantation improved OS for patients with a high but not a low LSC17 score. This study establishes the real-world value of the LSC17 score as a robust tool for risk assessment in AML and paves the way for its incorporation into routine clinical practice.

Acute myeloid leukemia (AML) is a heterogeneous malignancy with multiple subtypes and variable clinical outcomes driven by disease characteristics as well as the clinical status of the patient.1 2,3 While genomic classification has further rationalized risk stratification in AML, many challenges remain.4 The accurate assessment of survival outcomes in AML subtypes driven by various combinations of driver mutations and cytogenetic abnormalities presents a challenge to the treating physician.5

AML is sustained by a rare subpopulation of leukemia stem cells (LSC) believed to drive therapy resistance and relapse.6,7 The LSC17 gene expression score was developed based on functionally-defined LSC populations across the spectrum of AML subtypes.8 In multiple independent retrospective cohorts, the LSC17 score has been found to robustly discriminate between patients with significantly different outcomes.9–12 Higher-than-median LSC17 scores were associated with poor treatment response and survival outcomes in both uni-and multi-variable survival analyses, independent of commonly used prognostic factors including cytogenetic and molecular risk groups.

Robotic microfluidic platform brings AI to lipid nanoparticle design

AI has designed candidate drugs for antibiotic-resistant infections and genetic diseases. But efforts to incorporate AI into the design of lipid nanoparticles (LNPs), the revolutionary delivery vehicles behind mRNA therapies like the COVID-19 vaccines, have been much more limited.

Designing LNPs is especially challenging: Each formulation combines multiple lipid components whose ratios influence how the particle delivers genetic instructions inside cells. Scientists still lack a clear map connecting those chemical inputs to biological outcomes.

The reason? There simply isn’t enough data.

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